(428h) Role of Phospholipid Signaling in the Gradient Sensing Mechanism of Motile Cells

When motile cells are exposed to a chemoattractant gradient, they develop a morphological asymmetry or polarity consisting of a distinct front and back. The formation of the morphological polarity is driven by the spatial segregation of distinct sets of intracellular molecules to the front and the rear of the cell. The frontness molecules, which include Cdc42, Rac, PI3K, PI3Ps, Arp2/3, and F-actin, localize to the front of the cell where they coordinate the extension of an actin-rich structure called the lamellipod. The backness molecules, which include Rho, Rho kinase, PTEN, and myosin II, migrate to the rear of the cell where they are thought to activate cell contraction.

In general, the spatial segregation of the frontness/backness molecules and the resultant morphological polarization occurs even if the cells are exposed to a uniform chemoattractant profile. This phenomenon has been called spontaneous polarization to emphasize the fact that the cells polarize despite the absence of a perceptible external cue. . The existence of spontaneous polarization is reminiscent of the Turing instability in reaction-diffusion systems. This is exemplified by the so-called activator-inhibitor model, which contains a sluggish activator that is synthesized autocatalytically, and a labile inhibitor that impedes the growth of the activator. I'll present the data showing the existence of an activator in the gradient sensing mechanism of neutrophil-differentiated HL-60 cells. This activator is involved in a positive feedback loop in the phosphoinositide signaling pathways.